It is proposed to develop phospholipid vesicles (liposomes) as an efficient "carriers" systems for introducing pharmacologically active compounds into cells both in vitro and in vivo. It is well established in this and other laboratories that lipid vesicles are taken-up efficiently by cultured cells in vitro. The mechanism involves initial adsorption of vesicles to cell surface with subsequent endocytosis or fusion, which occur to various degrees and at different rates with various types of vesicles and cells. We plan to examine in detail the respective contributions from each alternative mechanism of uptake and to establish conditions which favor one or the other of the respective pathways. We will use various drug-containing lipid vesicles to enhance the cellular incorporation of several chemotherapeutic agents that are not taken up normally by living cells or have very short plasma half-life in vivo. We will incorporate drugs into vesicles, characterize their uptake in vitro and assay their biological effects. We will study, in vivo, the rate of clearance of different vesicles from the blood, their distribution in different tissues and their anti-tumor effects. We will also study their uptake and cytotoxic effects against various drug-resistant tumor cells. The composition and size of the vesicles will be varied in order to obtain maximal drug sequestration and minimal leakage, and optimal plasma clearance rate, uptake by cells and tissue distribution. In addition we will develop methods for making vesicles specifically targetted to specific cell types and tissues.